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Nat Commun. 2013;4:2410. doi: 10.1038/ncomms3410.

Drug screening in Scn1a zebrafish mutant identifies clemizole as a potential Dravet syndrome treatment.

Author information

1
1] Epilepsy Research Laboratory, Department of Neurological Surgery, University of California, San Francisco, Box 0520, 513 Parnassus Avenue San Francisco, California 94143, USA [2] Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, California 94143, USA.

Abstract

Dravet syndrome is a catastrophic pediatric epilepsy with severe intellectual disability, impaired social development and persistent drug-resistant seizures. One of its primary monogenic causes are mutations in Nav1.1 (SCN1A), a voltage-gated sodium channel. Here we characterize zebrafish Nav1.1 (scn1Lab) mutants originally identified in a chemical mutagenesis screen. Mutants exhibit spontaneous abnormal electrographic activity, hyperactivity and convulsive behaviours. Although scn1Lab expression is reduced, microarray analysis is remarkable for the small fraction of differentially expressed genes (~3%) and lack of compensatory expression changes in other scn subunits. Ketogenic diet, diazepam, valproate, potassium bromide and stiripentol attenuate mutant seizure activity; seven other antiepileptic drugs have no effect. A phenotype-based screen of 320 compounds identifies a US Food and Drug Administration-approved compound (clemizole) that inhibits convulsive behaviours and electrographic seizures. This approach represents a new direction in modelling pediatric epilepsy and could be used to identify novel therapeutics for any monogenic epilepsy disorder.

PMID:
24002024
PMCID:
PMC3891590
DOI:
10.1038/ncomms3410
[Indexed for MEDLINE]
Free PMC Article

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